Sulfonation modification of REDV peptides for directing cardiovascular cell fates

The Arginine-Glutamic acid-Aspartic acid-Valine (Arg-Glu-Asp-Val, REDV) peptide selectively binds endothelial cells but exhibits limited multifunctional bioactivity for cardiovascular applications. Sulfonation has been reported to confer multi-cellular regulatory functions to various biomolecules. In this study, sulfonated REDV peptides (S-REDV) with sulfur contents of 3.56 ± 0.10, 4.20 ± 0.23, 5.39 ± 0.13, and 5.98 ± 0.08 at.% were prepared by controlling the reaction time. Comprehensive cytocompatibility evaluations revealed that a moderate sulfonation degree (S-REDV-3) significantly enhanced human umbilical vein endothelial cell (HUVEC) proliferation, nitric oxide (NO) release and migration. Moreover, it restrained excessive smooth muscle cell (SMC) proliferation, preserved the contractile phenotype of SMCs, and drove macrophage polarization toward an anti-inflammatory phenotype. In contrast, excessive sulfonation resulted in structural degradation and compromised bioactivity. These results indicate that appropriately sulfonated REDV, particularly S-REDV-3, may serve as a promising bioactive peptide for surface functionalization of cardiovascular biomaterials.